All three projects of this program focus on critically testing the central hypothesis that chronic infusions of GDNF promote the regeneration and functional recovery of the nigrostriatal dopamine system. Project 3 utilizes quantitative morphometric procedures, immunocytochemistry, in stu hybridization, immunoautoradiographic procedures and retrograde tract tracing to analyze the recovery of the nigrostriatal dopamine system in parkinsonian rhesus monkeys receiving GDNF. The effects of chronic infusions into two CNS sites are critically tested, the lateral ventricle and the putamen. The analysis includes determining the consequences of interrupting trophic factor for four months and then reinstating GDNF infusion for eight weeks. The results from these studies, combined with the neurochemical analyses in Project 1 and the behavioral and functional MRI measures of Project 2, should advance our understanding of the factors underlying successful regeneration in the parkinsonian brain. In addition, these studies significantly contribute to developing the methodology for chronically delivering other tropic factors and therapeutic compounds into the CNS.